Feature Articles

Biomarkers Inform Cancer Research

A multidimensional analysis of genes mutated in breast cancer, which will probably end up with 12 to 40 drivers. [Edith Sanford Breast Cancer Institute]

Biomarkers—the essential fuel for personalized medicine—play an ever-growing role in drug discovery, clinical development, and, at least for cancer, in the clinic where genomic profiling of individual tumors often informs therapy selection.

Advancing assay technology, improving techniques for working with FFPE tissue samples, and multistakeholder collaborations are all driving factors.

“This is a pivotal time in cancer research,” said Brian Leyland-Jones, Ph.D., institute director at the Edith Sanford Breast Cancer Institute, and a speaker at GTC’s recent “Oncology Biomarkers” conference. “We’re going to see this emergence of targeted therapies against individual genomic drivers, whatever their disease is, and breast cancer will be one of the first areas.”

The Sanford institute uses systems biology approaches to identify biomarkers. “Looking at one level isn’t enough,” says Dr. Leyland-Jones. “We are applying several complementary molecular profiling methods to tumor bank specimens from several international clinical trials that include all of the major breast cancer subtypes.”

These biomarker sets are being used to predict short-term (such as pathologic complete response) and long-term (such as distant disease free survival and overall survival) outcomes, as well as guide treatment strategies, and identify potential therapeutic targets.

Among several key technologies being used are:

The whole-genome cDNA-mediated annealing, selection, extension, and ligation (WG-DASL) assay, which will enable the expression profiling of >24,000 protein-coding genes, is now available for use with FFPE specimens.

Genomic instability, a hallmark of tumor progression and poor prognosis, can be assessed by array CGH with ultra–high-density arrays containing 2 million features providing unprecedented genomic resolution. Also, SNP analysis can now be performed on arrays that assay 1 million SNP loci.

Genome-wide methylation arrays have become available to interrogate 27,578 CpG loci, covering more than 14,000 genes at single-nucleotide resolution.

Sanford also plans an initial study of 25 patients, “We will use several platforms (exome sequencing, RNAseq, various detailed protein arrays (e.g., phosphorylation arrays) to try to work out in 25 sequential patients in metastatic breast cancer what the individual drivers are,” explains Dr. Leland-Jones.

“Use of mouse models, including mouse avatars, will also be important. Past studies have suggested 10–13 pathway drivers including, for example, DNA repair, metabolism, and angiogenesis.

“I think it is going to be more complicated. It’s still anybody’s guess. Mine is that it’s going to be on the order of 30 to 40 pathways. No matter what it end ups being, I think treatment will require combinations of two or three agents for each of these subsets.”

Complex Biosignatures

Fast-moving efforts to identify multiple molecular drivers to divide cancer into more subtypes means biomarkers will become increasingly complex biosignatures that change over time under the influence of drug treatment.

It’s likely that a combination of tests, not just one, will be required to monitor and tailor therapies informed by these changing biosignatures over the course of the disease, said Matthew Morrison, Ph.D., biology manager, medical diagnostics, GE Healthcare.

“The vision as we see it is to bring together our know-how in molecular imaging (PET and SPECT) and combine this with in vitro diagnostics, bringing in the recent acquisition of Clarient and SeqWright to add pathology and next-generation sequencing platforms,” said Dr. Morrison.

He also discussed two experimental GE imaging agents, one targeted toward angiogenesis imaging and the other toward c-met expression, to gauge patient response to therapy.

“These experimental imaging agents, Fluciclatide (the GE RGD PET tracer) and GE-212 (the GE cMet PET tracer), are both being developed as tools to allow drug therapy selection and drug therapy monitoring. This is important at a number of levels,” he said.

Targeted cancer therapies are costly and work only in sub-populations. “New agents that allow better use of limited healthcare funds to give the treatment to the right patient are important, and in addition stopping treatment when it is not beneficial or even potentially harmful to the patient is important,” added Dr. Morrison.

AGP’s Theranostic Strategy

Roughly 40% of ER+ breast cancer patients treated with anti-estrogen agents become resistant to the therapy. A.G. Pharmaceutical (AGP) has shown that GP88 (progranulin) holds promise both as a marker for resistance and as a target for therapeutic intervention.

In a paper published earlier this year in Breast Cancer Research, AGP’s founder and CEO Ginette Serrero, Ph.D., and colleagues wrote, “The survival factor GP88 is a novel prognostic biomarker, predictive of recurrence risk and increased mortality for nonmetastatic ER+ IDC patients. Of importance, our data show that GP88 continues to be a prognostic factor even after five years.

“These results also provide evidence that GP88 provides prognostic information independent of tumor and clinical characteristics and would support prospective study to examine whether GP88 expression could help stratify patients with ER+ tumors for adjuvant therapy.”

AGP has developed two tests, one tissue based (IHC) and one for fluids (ELISA) to detect the levels of GP88. Because GP88 is such a strong driver of tumor biology, she said, “those two diagnostics tests can have a life of their own in the current standard of care. That was very important to us because if you develop a test that is only linked to a therapy, and your therapy fails, your test is never going to see the light of day either.

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